lignans and Asthma

Topics: Allergens; Anhydrides; Animals; Asthma; Disease Models, Animal; Dogs; Guinea Pigs; Haplorhini; Humans; Isocyanates; Lignans; Mice; Naphthols; Occupational Diseases; Platinum Compounds; Rabbits; Rats; Respiratory Hypersensitivity

This paper deals with the recent progress in the study of anti-PAF constituents of medicinal herbs. The structural modification, synthesis of analogs and pharmacophore model are also introduced in brief.

Topics: Animals; Asthma; Benzofurans; Diterpenes; Drugs, Chinese Herbal; Furans; Ginkgolides; Humans; Lactones; Lignans; Plant Extracts; Platelet Activating Factor

Topics: Asthma; Biomechanical Phenomena; Bronchial Provocation Tests; Bronchial Spasm; Bronchitis; Byssinosis; Cyanates; Dust; Edible Grain; Forecasting; Humans; Hypersensitivity; Insecticides; Lignans; Naphthols; Occupational Diseases; Organophosphorus Compounds; Prognosis; Reflex; Respiratory Function Tests; Respiratory Hypersensitivity; Serology; Skin Tests; Smoking; Terminology as Topic

Specific challenge tests with a suspected allergen in the workplace are standard to confirm the diagnosis of asthma. Facilities for sophisticated exposure tests are available only in a few institutions. A pilot study was carried out that used a novel approach for an occupational dust challenge test with a rotahaler.. Nine consecutive patients were enrolled in this study. Six of these proved to have asthma to red cedar by challenge tests with plicatic acid. They were challenged with a maximum dosage of 80 mg of red cedar dust and spruce dust (control) with a rotahaler on separate days in a single blinded manner. A positive reaction was defined as a fall in the forced expiratory volume in one second (FEV1) or the peak expiratory flow (PEF) after a challenge test of > or = 20% below the baseline value.. Three of the six patients who reacted to plicatic acid also had a positive response to red cedar dust delivered through a rotahaler. All three patients with a negative response to challenge with plicatic acid also showed a negative response to red cedar dust.. This pilot study showed that a positive challenge test with a rotahaler to deliver red cedar dust was specific in the diagnosis of red cedar asthma but a negative response could not rule out the diagnosis. The rotahaler has merits of being easy to operate, safe, inexpensive, and readily available. The usefulness of this method and its reproducibility have to be examined in a series of patients.

Topics: Adult; Asthma; Bronchial Provocation Tests; Dust; Forced Expiratory Volume; Humans; Lignans; Male; Middle Aged; Naphthols; Nebulizers and Vaporizers; Occupational Diseases; Peak Expiratory Flow Rate; Pilot Projects; Wood

Asthma is a persistent respiratory ailment that displays periodicity and is linked to the equilibrium of T cells. Several compounds obtained from Chinese herbal medicines display beneficial impacts on T cell regulation and the attenuation of inflammatory mediator synthesis. Schisandrin A, an active lignan derived from the Schisandra fruit, exhibits anti-inflammatory characteristics. In the present study, the network analysis conducted revealed that the nuclear factor-kappaB (NF-κB) signaling pathway is likely a prominent contributor to the anti-asthmatic effects of schisandrin A. In addition, it has been established that the inhibition of cyclooxygenase 2 (COX-2/PTGS2) is likely a significant factor in this process. The results of in vitro experiments have substantiated that schisandrin A can effectively lower the expression of COX-2 and inducible nitric oxide synthase (iNOS) in 16 HBE cells and RAW264.7 cells in a manner that is dependent on the dosage administered. It was able to effectively reduce the activation of the NF-κB signaling pathway while simultaneously improving the injury to the epithelial barrier function. Furthermore, an investigation utilizing immune infiltration as a metric revealed an inequity in Th1/Th2 cells and a surge in Th2 cytokines in asthma patients. In the OVA-induced asthma mice model, it was observed that schisandrin A treatment effectively suppressed inflammatory cell infiltration, reduced the Th2 cell ratio, inhibited mucus secretion, and prevented airway remodeling. To summarize, the administration of schisandrin A has been found to effectively alleviate the symptoms of asthma by impeding the production of inflammation, which includes reducing the Th2 cell ratio and improving the integrity of the epithelial barrier function. These findings offer valuable insights into the potential therapeutic applications of schisandrin A for the treatment of asthma.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Inflammation; Lignans; Mice; Mice, Inbred BALB C; NF-kappa B; Ovalbumin

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Asthma; Cyclooctanes; Dendritic Cells; Disease Models, Animal; Forkhead Transcription Factors; Heme Oxygenase-1; Hypersensitivity; Immunoglobulin E; Immunomodulating Agents; Lignans; Mice; Mice, Inbred BALB C; Polycyclic Compounds; Respiratory Hypersensitivity; T-Lymphocytes, Regulatory; Th2 Cells

Topics: Animals; Apoptosis; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Dioxoles; Humans; Inflammation; Interleukin-4; Lignans; Lung; Mice; Mitochondria; Mitophagy; Protein Kinases; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases

Asthma is a chronic inflammatory disorder of the airways. Schisandrin B (SB) is the main effective component. This study investigated the effects of SB on airway inflammation and airway remodeling in asthma. The rat model of asthma was established. The rats were treated with SB to evaluate the effects of SB on airway inflammation, airway remodeling, NLRP3 inflammasome activation, and pyroptosis. Alveolar macrophages of rats were isolated, and the macrophage inflammatory model was established by lipopolysaccharide (LPS) induction. The LPS-induced macrophages were treated with SB. The binding relationship between miR-135a-5p and TPRC1 was analyzed. LPS + SB-treated macrophages were transfected with miR-135a-5p inhibitor. The expressions of key factors of the STAT3/NF-κB pathway were detected. SB reduced airway inflammation and airway remodeling in asthmatic rats. SB inhibited NLRP3 inflammasome activation and reduced pyroptosis in asthmatic rats and LPS-induced macrophages. SB reversely regulated the miR-135a-5p/TRPC1 axis. Downregulation of miR-135a-5p attenuated the inhibitory effect of SB on NLRP3 inflammasome activation. SB inhibited the STAT3/NF-κB pathway via the miR-135a-5p/TRPC1 axis. In conclusion, SB inhibited NLRP3 inflammasome activation and reduced pyroptosis via the miR-135a-5p/TRPC1/STAT3/NF-κB axis, thus alleviating airway inflammation and airway remodeling in asthma. This study may confer novel insights for the management of asthma.

Topics: Airway Remodeling; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Cells, Cultured; Cyclooctanes; Disease Models, Animal; Female; Inflammasomes; Lignans; Lung; Macrophages, Alveolar; MicroRNAs; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Pneumonia; Polycyclic Compounds; Pyroptosis; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor; TRPC Cation Channels

Asthma is a complex inflammatory disorder that plagues a large number of people. Schisandrin B is an active ingredient of the traditional Chinese herbal medicine Schisandra with various proven physiological activities such as anti-inflammatory and antioxidant activities. In this study, we explored the anti-inflammatory and antioxidant effects and provided the mechanistic insights into the activity of schisandrin B in a mouse model of ovalbumin- (OVA-) induced allergic asthma.. Male BALB/c mice were sensitized and challenged with OVA to induce asthma and treated with various doses (15 mg/kg, 30 mg/kg, and 60 mg/kg) of SCH to alleviate the features of allergic asthma, airway hyperresponsiveness, inflammatory response, OVA-specific immunoglobulin (Ig)E level, and pathological injury.. Schisandrin B significantly attenuated the airway hyperresponsiveness induced by OVA. Moreover, schisandrin B administration suppressed inflammatory responses, reduced the level of IgE, and attenuated pathological injury. Mechanistically, schisandrin B treatment promoted the activation of nuclear erythroid 2-related factor 2 (Nrf2), but suppressed the stimulation of the NF-. Taken together, our study suggests that schisandrin B attenuates the features of asthmatic lungs by inhibiting the NF-

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cyclooctanes; Disease Models, Animal; Humans; Lignans; Lung; Male; Mice; NF-E2-Related Factor 2; NF-kappa B; Ovalbumin; Oxidative Stress; Polycyclic Compounds; Signal Transduction; Specific Pathogen-Free Organisms

Eugenol, a common phenylpropanoid derivative found in different plant species, has well-described anti-inflammatory effects associated with the development of occupational hypersensitive asthma. Dehydrodieugenol, a dimeric eugenol derivative, exhibits anti-inflammatory and antioxidant activities and can be found in the Brazilian plant species Nectandra leucantha (Lauraceae). The biological effects of dehydrodieugenol on lung inflammation remain unclear.. This study aimed to investigate the effects of eugenol and dehydrodieugenol isolated from N. leucantha in an experimental model of asthma.. In the present work, the toxic effects of eugenol and dehydrodieugenol on RAW 264.7 cells and their oxidant and inflammatory effects before lipopolysaccharide (LPS) exposure were tested. Then, male BALB/c mice were sensitized with ovalbumin through a 29-day protocol and treated with vehicle, eugenol, dehydrodieugenol or dexamethasone for eight days beginning on the 22nd day until the end of the protocol. Lung function; the inflammatory profile; and the protein expression of ERK1/2, JNK, p38, VAChT, STAT3, and SOCS3 in the lung were evaluated by immunoblotting.. Eugenol and dehydrodieugenol were nontoxic to cells. Both compounds inhibited NO release and the gene expression of IL-1β and IL-6 in LPS-stimulated RAW 264.7 cells. In OVA-sensitized animals, dehydrodieugenol reduced lung inflammatory cell numbers and the lung concentrations of IL-4, IL-13, IL-17, and IL-10. These anti-inflammatory effects were associated with inhibition of the JNK, p38 and ERK1/2, VAChT and STAT3/SOCS3 pathways. Moreover, treatment with dehydrodieugenol effectively attenuated airway hyperresponsiveness.. The obtained data demonstrate, for the first time, that dehydrodieugenol was more effective than eugenol in counteracting allergic airway inflammation in mice, especially its inhibition of the JNK, p38 and ERK1/2, components of MAPK pathway. Therefore, dehydrodieugenol can be considered a prototype for the development of new and effective agents for the treatment of asthmatic patients.

Topics: Animals; Asthma; Dose-Response Relationship, Drug; Eugenol; Lauraceae; Lignans; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Plant Extracts; Pneumonia; RAW 264.7 Cells; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein

In the present work, the anti-inflammatory and antiasthmatic potential of biseugenol, isolated as the main component from

Topics: Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Biological Availability; Biphenyl Compounds; Computer Simulation; Disease Models, Animal; Granulocytes; Inflammation; Lignans; Linear Models; Male; Mice, Inbred BALB C; Phenyl Ethers; Respiratory Function Tests; Respiratory Hypersensitivity

We established a mouse model of allergic asthma by sensitizing with chicken ovalbumin. The volatile oils and decoctions from raw, wine- and vinegar-steamed Schisandra chinensis fruits were intragastrically administrated to the mice. Atomization, serum IgE, IL-2, IL-4 and IFN-γ in the lung homogenates and pathological sections were evaluated to compare the effect of these volatile oils and decoctions on allergic asthma in mice. The results showed that all Schisandra volatile oils could significantly suppress allergic asthma in mice. Raw Schisandra volatile oil was most effective followed by volatile oils extracted from wine-steamed and vinegar-steamed Schisandra. The decoctions had no significant impact. Our findings demonstrated that volatile oil was the active ingredient in Schisandra, and raw Schisandra could be used to prevent cough and asthma.

Topics: Animals; Asthma; Cyclooctanes; Fruit; Hypersensitivity; Lignans; Male; Mice; Oils, Volatile; Ovalbumin; Plant Extracts; Polycyclic Compounds; Schisandra

Our previous study revealed that the ethanolic extract of Justicia procumbens ameliorates ovalbumin-induced airway inflammation and airway hyper-responsiveness in a mouse model of asthma. However, the mechanism of action of the extract remains unknown. In this study, we prepared DW2008S, an optimized and standardized powder extracted from J. procumbens using anhydrous ethanol, and investigated its anti-asthmatic effect and mechanism of action. Our results showed that DW2008S contains two major ingredients, justicidin A (JA) and justicidin B (JB), which selectively inhibit T helper 2 (Th2) cell responses in concanavalin A-activated spleen cells and polarized Th2 cells. Blockade of T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) using a neutralizing antibody also selectively inhibited Th2 cell responses. Furthermore, DW2008S regulated TIGIT expression in the mice and cultured cells. Additionally, DW2008S and JA antagonized human adenosine receptor A

Topics: Animals; Anti-Asthmatic Agents; Antibodies, Neutralizing; Asthma; Cyclic Nucleotide Phosphodiesterases, Type 4; Dioxolanes; Disease Models, Animal; Female; Inflammation; Justicia; Lignans; Mice, Inbred BALB C; Plant Extracts; Protective Agents; Receptor, Adenosine A3; Receptors, Immunologic; Th2 Cells

Allergic asthma is a disease that pathologically characterized by eosinophilia infiltration, airway inflammation and hyper responsiveness. In this study, we evaluated the anti-inflammatory and anti-allergy possibilities of honokiol, a bi-phenolic compound obtained from species of the genus Magnolia, which has long been involved in traditional Chinese prescriptions for asthma-related lung diseases, in an ovalbumin-induced mouse model of allergic asthma. We found honokiol significantly inhibited the eosinophilia infiltration, reduced the airway inflammation and suppressed the production of inflammatory cytokines) as well as the IgE in serum. Moreover, MMP-9 and? (IL-4 and IFN- NF-κB were found to be involved in the honokiol induced biological process. These results suggested that honokiol may be a possible candidate in the treatment of lung asthma related diseases.

Topics: Administration, Oral; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Asthma; Biphenyl Compounds; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Female; Immunoglobulin E; Inflammation; Lignans; Mice, Inbred BALB C; Respiratory System

To explore the therapeutic effect of honokiol on particulate matter 2.5 (PM2.5)-induced lung injury in asthmatic mice and the possible mechanisms.
 Methods: A total of 32 BALB/C mice were randomly divided into four groups: a normal saline group, a model group, a PM2.5 group and a honokiol group (n=8 in each group). The asthma mouse model was established by ovalbumin treatment. The mice were treated with physiological saline, ovalbumin, PM2.5 and honokiol, respectively. Lung tissues and serum were collected. The pathological changes of lung tissues were evaluated. The levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and serum were measured and the expressions of Toll like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), retinoid-related orphan receptor gamma-t (RORγt) and forkhead box protein 3 (Foxp3) in lung tissues were detected.
 Results: 1) The lung tissues of mice in the asthma group showed obvious pathological changes and inflammatory state, suggesting that the asthma model was established successfully. PM2.5 could aggravate the pathological condition of inflammatory injury in lung tissues in asthmatic mice. 2) Compared to the PM2.5 group, the pathological symptoms in the lung tissues were alleviated in the honokiol group and the percentage of inflammatory cells in BALF and the levels of inflammatory cytokines in BALF and serum were significantly reduced (all P<0.05). 3) Compared to the PM2.5 group, the expressions of TLR4, NF-κB (p-p65) and RORγt in lung tissues were significantly decreased, while the expression of Foxp3 was increased; the ratio of RORγt/Foxp3 was also decreased in the honokiol group (all P<0.05).
 Conclusion: Honokiol can resist lung injury induced by PM2.5 in asthmatic mice. These effects are through inhibiting TLR4-NF-κB pathway-mediated inflammatory response or regulating the balance of Th17/Treg cells.. 目的：探究和厚朴酚对颗粒物2.5(particulate matter 2.5，PM2.5)诱导的哮喘小鼠肺损伤的治疗作用及其可能的作用机制。方法：32只BALB/C小鼠随机分为生理盐水组、模型组、PM2.5组和厚朴酚组，每组8只。使用卵清蛋白诱导哮喘小鼠模型，分别采用生理盐水、卵清蛋白、PM2.5和和厚朴酚处理，收集各组小鼠肺组织和血清，检测小鼠肺组织的病理损伤状态、支气管肺泡灌洗液(bronchoalveolar lavage fluid，BALF)和血清中炎性因子的表达水平，以及肺组织中Toll样受体4(Toll like receptor 4，TLR4)、核因子κB(nuclear factor kappa B，NF-κB)、维甲酸相关核孤儿受体γt(retinoid-related orphan receptor gamma-t，RORγt)和叉头状转录蛋白3(forkhead box protein 3，Foxp3)的蛋白表达水平。结果：1)模型组小鼠肺组织出现明显病理损伤和炎性状态，提示哮喘模型构建成功。PM2.5能够加重哮喘小鼠的肺组织病理损伤和炎性状态；2)与PM2.5组比较，和厚朴酚组小鼠肺组织的病理损伤状态得到缓解，BALF中炎性细胞减少，炎性因子水平降低(均P<0.05)。3)与PM2.5组比较，和厚朴酚组小鼠肺组织中TLR4，NF-κB(p-p65)和RORγt的表达减少，Foxp3表达水平增加，且RORγt/Foxp3比值减少(均P<0.05)。结论：和厚朴酚能够抵抗PM2.5诱导哮喘小鼠的肺损伤，这一方面可能是通过抑制TLR4-NF-κB信号通路介导的炎症反应，另一方面可能是通过影响T辅助细胞17/调节性T细胞平衡的方式来实现的。.

Topics: Animals; Asthma; Biphenyl Compounds; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Drugs, Chinese Herbal; Inflammation Mediators; Lignans; Lung; Lung Injury; Mice; Mice, Inbred BALB C; NF-kappa B; Ovalbumin; Particulate Matter; Random Allocation; Toll-Like Receptor 4

Topics: Adult; Asthma; Biomarkers; Bronchial Provocation Tests; Gene Expression; Humans; Lignans; Male; Middle Aged; Naphthols; Northwestern United States; Occupational Diseases; Thuja

The mechanism of Schisandrin B on the proliferation and migration of airway smooth muscle cells (ASMCs) in asthmatic rats was explored.. SD rats were divided into three groups: control (group 1), model (group 2) and model + Schisandrin B (group 3). miR-150 and lncRNA BCYRN1 levels were measured by qRT-PCR. The combination of BCYRN1 and miR-150 was detected by RNA pull down. ASMCs' viability/proliferation/migration were examined by WST-1 assay and 24-well Transwell system.. Schisandrin B up-regulated miR-150 expression and down-regulated BCYRN1 expression in sensitized rats. Schisandrin B reversed the expression of miR-150 and BCYRN1 in MV-treated ASMCs. In addition, Schisandrin B inhibited the viability, proliferation and migration of MV-induced ASMCs. We also found miR-150 inhibited BCYRN1 expression which was proved by experiments using ASMCs transfected with miR-150 inhibitor.. Schisandrin B increased miR-150 expression and decreased BCYRN1, and BCYRN1 expression was inhibited by miR-150, which indicated that Schisandrin B could regulate BCYRN1 through miR-150.

Topics: Animals; Asthma; Cell Movement; Cell Proliferation; Cells, Cultured; Cyclooctanes; Disease Models, Animal; Down-Regulation; Female; Lignans; MicroRNAs; Myocytes, Smooth Muscle; Polycyclic Compounds; Rats, Sprague-Dawley; RNA, Long Noncoding

meso-Dihydroguaiaretic acid (MDGA), which is a dibenzylbutane lignin isolated from the ethyl acetate fraction of Saururus chinensis, has various biological activities, including anti-oxidative, anti-inflammatory, anti-bacterial, and neuroprotective effects. However, no report has examined the potential anti-asthmatic activity of MDGA. In this study, we evaluated the protective effects of MDGA on asthmatic responses, particularly airway inflammation and mucus hypersecretion in an ovalbumin (OVA)-induced murine model of asthma. Intragastric administration of MDGA significantly lowered the productions of interleukin (IL)-4, IL-5, IL-13, tumor necrosis-α (TNF-α), eotaxin, monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and immunoglobulin (Ig)E in bronchoalveolar lavage fluid (BALF), plasma, or lung tissues. Histological studies showed that MDGA inhibited OVA-induced inflammatory cell infiltration and mucus production in the respiratory tract. Moreover, MDGA markedly attenuated the OVA-induced activations of nuclear factor kappa B (NF-κB), extracellular-signal-regulated kinases 1/2 (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK). Together, these results suggest that MDGA effectively inhibits airway inflammation and mucus hypersecretion by downregulating the levels of T helper 2 (Th2) cytokines, chemokines, and adhesion molecules, and inhibiting the activations of NF-κB and MAPKs.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Cell Movement; Chemokine CCL2; Cytokines; Female; Guaiacol; Humans; Immunoglobulin E; Lignans; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; NF-kappa B; Pneumonia; Saururaceae; Th2 Cells; Vascular Cell Adhesion Molecule-1

Airway smooth muscle cell (ASMC) was known to involve in the pathophysiology of asthma. Schisandrin B was reported to have anti-asthmatic effects in a murine asthma model. However, the molecular mechanism involving in the effect of Schisandrin B on ASMCs remains poorly understood. Sprague-Dawley rats were divided into three groups: rats as the control (Group 1), sensitized rats (Group 2), sensitized rats and intragastric-administrated Schisandrin B (Group 3). The expression of miR-135a and TRPC1 was detected in the rats from three groups. Platelet-derived growth factor (PDGF)-BB was used to induce the proliferation of isolated ASMCs, and the expression of miR-135a and TRPC1 was detected in PDGF-BB-treated ASMCs. Cell viability was examined in ASMCs transfected with miR-135a inhibitor or si-TRPC1. The expression of TRPC1 was examined in A10 cells pretreated with miR-135a inhibitor or miR-135a mimic. In this study, we found that Schisandrin B attenuated the inspiratory and expiratory resistances in sensitized rats. Schisandrin B upregulated the mRNA level of miR-135a and decreased the expression of TRPC1 in sensitized rats. In addition, Schisandrin B reversed the expression of miR-135a and TRPC1 in PDGF-BB-induced ASMCs. Si-TRPC1 abrogated the increasing proliferation of ASMCs induced by miR-135a inhibitor. We also found that miR-135a regulated the expression of TRPC1 in the A10 cells. These results demonstrate that Schisandrin B inhibits the proliferation of ASMCs via miR-135a suppressing the expression of TRPC1.

Topics: Airway Remodeling; Animals; Apoptosis; Asthma; Cell Proliferation; Cell Survival; Cells, Cultured; Cyclooctanes; Lignans; Male; MicroRNAs; Myocytes, Smooth Muscle; Polycyclic Compounds; Random Allocation; Rats; Rats, Sprague-Dawley; TRPC Cation Channels; Up-Regulation

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asthma; Bacteria; Child; Diet; Female; Humans; Isoflavones; Lignans; Male; Middle Aged; Nutrition Surveys; Respiratory Sounds; Young Adult

Asthma is a heterogenetic disorder characterized by chronic inflammation with variable airflow obstruction and airway hyper-responsiveness. As the most potent and popular bronchodilators, β2 adrenergic receptor (β2 AR) agonists bind to the β2 ARs that are coupled via a stimulatory G protein to adenylyl cyclase, thereby improving cAMP accumulation and resulting in airway smooth muscle relaxation. We previously demonstrated arctigenin had a synergistic function with the β2 AR agonist, but the target for this remained elusive.. Chemical proteomics capturing was used to enrich and uncover the target of arctigenin in human bronchial smooth muscle cells, and reverse docking and molecular dynamic stimulation were performed to evaluate the binding of arctigenin and its target. In vitro enzyme activities and protein levels were demonstrated with special kits and Western blotting. Finally, guinea pig tracheal muscle segregation and ex vivo function were analysed.. Arctigenin bound to PDK1 with an ideal binding free energy -25.45 kcal/mol and inhibited PDK1 kinase activity without changing its protein level. Additionally, arctigenin reduced PKB/Akt-induced phosphorylation of PDE4D, which was first identified in this study. Attenuation of PDE4D resulted in cAMP accumulation in human bronchial smooth muscle. The inhibition of PDK1 showed a synergistic function with β2 AR agonists and relaxed the constriction of segregated guinea pig tracheal muscle.. The PDK1/Akt/PDE4D axis serves as a novel asthma target, which may benefit airflow obstruction.

Topics: 3-Phosphoinositide-Dependent Protein Kinases; Adrenergic beta-2 Receptor Agonists; Animals; Anti-Asthmatic Agents; Asthma; Blotting, Western; Bronchi; Cyclic Nucleotide Phosphodiesterases, Type 4; Drug Synergism; Furans; Guinea Pigs; Humans; Lignans; Myocytes, Smooth Muscle; Proto-Oncogene Proteins c-akt; Signal Transduction

Homoegonol is a lignan derived from styraxlignolide A, which was isolated from Styrax japonica, a medicinal plant widely used for treatment of inflammatory diseases in Korea. We investigated the efficacy of homoegonol for the treatment of allergic asthma using an ovalbumin (OVA)-induced murine asthma model. The mice were sensitized through intraperitoneal injections of OVA on days 0 and 14. On days 21, 22 and 23 after the initial OVA sensitization, the mice were received OVA airway challenge. Homoegonol was administered by oral gavage at a dose of 30 mg/kg 1 h prior to the OVA challenge. The homoegonol-treated mice exhibited reduced inflammatory cell counts and Th2 cytokines in BALF, AHR, and IgE in the serum compared with the OVA-sensitized/challenged mice. The histological analysis of the lung tissue revealed that the administration of homoegonol attenuated the airway inflammation and the mucus overproduction in airway epithelial lesions induced by OVA through a reduction in expression of inducible nitric oxide synthase and matrix metalloproteinase-9. These findings indicate that homoegonol effectively suppresses the asthmatic responses induced by OVA challenge and suggests that homoegonol exhibits potential as therapeutic drug for allergic asthma.

Topics: Administration, Oral; Airway Resistance; Animals; Anisoles; Anti-Allergic Agents; Anti-Asthmatic Agents; Asthma; Benzofurans; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Down-Regulation; Female; Immunoglobulin E; Lignans; Lung; Matrix Metalloproteinase 9; Mice, Inbred BALB C; Nitric Oxide Synthase Type II; Ovalbumin; Respiratory Mucosa; Specific Pathogen-Free Organisms

Allergic asthma is a lifelong airway condition that affects people of all ages. In recent decades, asthma prevalence continues to increase globally, with an estimated number of 250,000 annual deaths attributed to the disease. Although inhaled corticosteroids and β-adrenergic receptor agonists are the primary therapeutic avenues that effectively reduce asthma symptoms, profound side effects may occur in patients with long-term treatments. Therefore, development of new therapeutic strategies is needed as alternative or supplement to current asthma treatments. Sesamin is a natural polyphenolic compound with strong anti-oxidative effects. Several studies have reported that sesamin is effective in preventing hypertension, thrombotic tendency, and neuroinflammation. However, it is still unknown whether sesamin can reduce asthma-induced allergic inflammation and airway hyperresponsiveness (AHR). Our study has revealed that sesamin exhibited significant anti-inflammatory effects in ovalbumin (OVA)-induced murine asthma model. We found that treatments with sesamin after OVA sensitization and challenge significantly decreased expression levels of interleukin-4 (IL-4), IL-5, IL-13, and serum IgE. The numbers of total inflammatory cells and eosinophils in BALF were also reduced in the sesamin-treated animals. Histological results demonstrated that sesamin attenuated OVA-induced eosinophil infiltration, airway goblet cell hyperplasia, mucus occlusion, and MUC5AC expression in the lung tissue. Mice administered with sesamin showed limited increases in AHR compared with mice receiving vehicle after OVA challenge. OVA increased phosphorylation levels of IκB-α and nuclear expression levels of NF-κB, both of which were reversed by sesamin treatments. These data indicate that sesamin is effective in treating allergic asthma responses induced by OVA in mice.

Topics: Active Transport, Cell Nucleus; Allergens; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Dioxoles; Eosinophils; Immunoglobulin E; Lignans; Lung; Male; Mice, Inbred BALB C; Mucus; NF-kappa B; Th2 Cells

Chemokines play important roles in the pathogenesis of asthmatic inflammation. Sesamin, a class of phytoestrogen isolated from sesame seed Sesamum indicum, is recently regarded as an anti-inflammatory agent. However, the effects of sesamin on asthma-related chemokines are unknown. To this end, we investigated the effects of sesamin on the expression interferon-γ-inducible protein-10 (IP-10/CXCL10), macrophage-derived chemokine (MDC/CCL22), growth-related oncogene-α (GRO-α/CXCL1) and tumor necrosis factor (TNF)-α in human monocytes.. Cells were pretreated with sesamin before lipopolysaccharide (LPS) stimulation. IP-10, MDC, GRO-α and TNF-α were measured by ELISA. Involved receptors and intracellular signaling were investigated by receptor antagonists, pathway inhibitors, western blotting and chromatin immunoprecipitation.. Sesamin suppressed LPS-induced MDC in THP-1 and human primary monocytes. Sesamin suppressed LPS-induced IP-10 in THP-1 cells, but not human primary monocytes. Sesamin had no effects on LPS-induced GRO-α and TNF-α expression in THP-1 and human primary monocytes. The suppressive effect of sesamin on MDC was reversed by the estrogen receptor (ER) and peroxisomal proliferator-activated receptor (PPAR)-α antagonists. Sesamin suppressed LPS-induced phosphorylation of mitogen-activated protein kinase (MAPK)-p38 and nuclear factor kappa B (NFκB)-p65. Sesamin suppressed histone H3/H4 acetylation in the MDC promoter region.. Sesamin suppressed LPS-induced MDC expression via the ER, the PPAR-α, the MAPK-p38 pathway, the NFκB-p65 pathway and the epigenetic regulation. Sesamin may have therapeutic potential in preventing and treating asthma.

Topics: Anti-Inflammatory Agents; Asthma; Cell Line, Tumor; Chemokine CCL22; Chemokine CXCL1; Chemokine CXCL10; Dioxoles; Epigenesis, Genetic; Histones; Humans; Lignans; Lipopolysaccharides; Monocytes; p38 Mitogen-Activated Protein Kinases; Phosphorylation; PPAR alpha; Promoter Regions, Genetic; Receptors, Estrogen; Seeds; Sesamum; Signal Transduction; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Topics: Adiponectin; Adult; Antigens, Plant; Asthma; Body Mass Index; Bronchial Provocation Tests; Dust; Eosinophilia; Forced Expiratory Volume; Humans; Lignans; Male; Methacholine Chloride; Middle Aged; Naphthols; Occupational Diseases; Occupational Exposure; Sputum; Thuja; Young Adult

Classical Chinese pharmacopeias describe numerous excellent herbal formulations, and each prescription is an outstanding pool of effective compounds for drug discovery. Clarifying the bioactivity of the combined mechanisms of the ingredients in complex traditional Chinese medicine formulas is challenging. A classical formula known as Qingfei Xiaoyan Wan, used clinically as a treatment for prevalent chronic lung disease, was investigated in this work. A mutually enhanced bioactivity-guided ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) characterization system was proposed, coupled with a dual-luciferase reporter assay for β2AR-agonist cofactor screening. Arctiin, arctigenin, descurainoside and descurainolide B, four lignin compounds that showed synergistic bronchodilation effects with ephedrine, were revealed. The synergistic mechanism of arctigenin with the β2ARagonist involved with the reduction of free Ca2+ was clarified by a dual-luciferase reporter assay for intracellular calcium and the Ca2+ indicator fluo-4/AM to monitor changes in the fluorescence. The relaxant and contractile responses of airway smooth muscle are regulated by crosstalk between the intracellular cAMP and calcium signaling pathways. Our data indicated the non-selective βAR agonist ephedrine as the principal bronchodilator of the formula, whereas the lignin ingredients served as adjuvant ingredients. A greater understanding of the mechanisms governing the control of these pathways, based on conventional wisdom, could lead to the identification of novel therapeutic targets or new agents for the treatment of asthma and COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Animals; Asthma; Bronchodilator Agents; Calcium; Cell Line; Chromatography, High Pressure Liquid; Chronic Disease; Disease Models, Animal; Drug Synergism; Drugs, Chinese Herbal; Ephedrine; Flavonoids; Furans; Glucosides; Guinea Pigs; Humans; Lactones; Lignans; Lung Diseases; Medicine, Chinese Traditional; Myocytes, Smooth Muscle; Trachea

Macelignan isolated from Myristica fragrans Houtt. is widely used for spice and flavoring for foods, and has been reported to have anti-inflammatory activity. The aim of this study was to investigate the effects of macelignan on allergic lung inflammation with a murine model of experimental asthma.. Fungal protease mixed with chicken egg ovalbumin allergen was used as a challenge to induce murine experimental asthma. To determine its effects on allergy and inflammation, macelignan was administered orally during allergen challenge, and the symptoms of allergic asthma and its underlined mechanisms were examined.. Treatment with macelignan attenuated eosinophilic airway inflammation and airway hyper-responsiveness. With the administration of macelignan, interleukin-4 (IL-4) producing cells, but not interferon-γ (IFN-γ) or IL-17 producing cells, were diminished in the lungs. Additionally, activation of the T helper type 2 (Th2) cell-specific master transcription factor, GATA3 was decreased with macelignan treatment. Finally, production of IL-4 but not IFN-γ or IL-17, by CD4(+) T cells was reduced with stimulation when combined with the administration of macelignan.. Our data show that macelignan has anti-inflammatory effects on Th2 cell-mediated allergic lung inflammation and could potentially provide a novel preventative and/or therapy for the treatment of allergic diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Bronchial Hyperreactivity; CD4-Positive T-Lymphocytes; Disease Models, Animal; Female; GATA3 Transcription Factor; Interleukin-4; Lignans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myristica; Plant Extracts; Th2 Cells

This study aims to clarify out the anti-inflammatory mechanism of Qingfei Xiaoyan Wan. Chemical constituents of Qingfei Xiaoyan Wan identified by UPLC Q-TOF, were submit to Molinspiration, PharmMapper and KEGG bioinformatics softwares for predicting their absorption parameters, target proteins and related pathways respectively; and the gene chip and real time-PCR were carried out to investigate the expression of inflammatory genes on lung tissue of guinea pigs or human bronchial epithelial cell lines. The predicted results showed that 19 of the 24 absorbable constituents affected at 9 inflammation-related pathways through 11 protein targets; Qingfei Xiaoyan Wan treatment can significantly reduce the infiltration of cytokines through ERK1 gene and 5 inflammatory pathways (Focal adhesion, Fc epsilon RI, Toll-like receptors, NK cell-mediated cytotoxic, and ERK/MAPK). The results of real time-PCR further confirmed that the anti-inflammatory effects of Qingfei Xiaoyan Wan were due to active ingredients such as arctigenin, cholic acid and sinapic acid intervened focal adhesion, Fc epsilon RI signaling and ERK/MAPK pathways. The novel approach of 'drug-target-pathway' will present an effective strategy for the study of traditional Chinese medicines.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Cell Line; Cholic Acid; Coumaric Acids; Cytokines; Drug Combinations; Drugs, Chinese Herbal; Epithelial Cells; Female; Furans; Guinea Pigs; Humans; Inflammation; Lignans; Lung; Male; MAP Kinase Signaling System; Random Allocation; Receptors, IgE; Toll-Like Receptors

It was reported previously that dibenzylbutyrolactone lignans from Forsythia viridissima fruits, which are traditional medicines for the treatment of inflammatory diseases, have antiinflammatory effects. In this study, the effects on the immediate-phase response (IAR) and late-phase response (LAR) following aerosolized-ovalbumin challenge in ovalbumin-sensitized guinea-pigs were evaluated by measuring the specific airway resistance (sRaw), recruitment of leukocytes and chemical mediators in the bronchoalveolar lavage fluids (BALF) as well as a histopathological survey. Arctiin and matairesinol at 12.5 mg/kg significantly (p < 0.05) decreased sRaw by 51.83% and 43.15% in IAR and by 47.41% and 35.43% in LAR, respectively, whereas arctigenin at 25 mg/kg was significantly active, compared with the controls. Furthermore, arctiin and arctigenin dose-dependently inhibited histamine, and the activities of phospholipase A₂ (PLA₂) and eosinophil peroxidase (EPO) in BALF, respectively, whereas matairesinol inhibited EPO and PLA₂ at 12.5 mg/kg and histamine at 50 mg/kg, in addition, they moderately improved the infiltration of eosinophils, compared with controls. Dexamethasone, cromolyn and salbutamol significantly inhibited sRaw in both IAR and LAR, and the recruitment of leukocytes and chemical mediators, whereas salbutamol did not alter chemical mediators, in BALF. These results indicate the three lignans have antiasthmatic effects which were less active than those of the reference drugs.

Topics: 4-Butyrolactone; Airway Resistance; Albuterol; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cromolyn Sodium; Dexamethasone; Disease Models, Animal; Eosinophil Peroxidase; Forsythia; Fruit; Guinea Pigs; Lignans; Male; Molecular Structure; Ovalbumin; Phospholipases A2; Plant Extracts

Chronic airway inflammation is a hallmark of asthma, which is an immune-based disease. We evaluated the ability of saucerneol D, a tetrahydrofuran-type sesquilignan isolated from Saururus chinensis, to regulate airway inflammation in an ovalbumin (OVA)-induced airway inflammation model. Furthermore, we determined whether heme oxygenase (HO)-1 was required for the protective activity of saucerneol D. The airways of OVA-sensitized mice exposed to an OVA challenge developed eosinophilia and mucus hypersecretion and exhibited increased cytokine levels. Mice were administered saucerneol D orally at doses of 20 and 40mg/kg once daily on days 26-30. Saucerneol D administered orally significantly inhibited the number of OVA-induced inflammatory cells and the production of immunoglobulin E as well as Th2-type cytokines. Histopathology studies revealed a marked decrease in lung inflammation and goblet cell hyperplasia after saucerneol D treatment. In addition, saucerneol D induced HO-1 and led to a marked decrease in OVA-induced reactive oxygen species and malondialdehyde and an increase in superoxide dismutase and glutathione in lung tissues. These antioxidant effects were correlated with HO-1 induction. In our experiments, saucerneol D treatment reduced airway inflammation and suppressed oxidative stress in an OVA-induced asthma model.

Topics: Animals; Anti-Asthmatic Agents; Antioxidants; Asthma; Cells, Cultured; Cytokines; Disease Models, Animal; Female; Heme Oxygenase (Decyclizing); Humans; Immunoglobulin E; Lignans; Mice; Mice, Inbred BALB C; Pneumonia; Reactive Oxygen Species; Saururaceae; Th1-Th2 Balance

Asthma comprises a triad of reversible airway obstruction, bronchial smooth muscle cell hyperreactivity to bronchoconstrictors, and chronic bronchial inflammation. Clinical and experimental findings have established eosinophilia as a sign of allergic disorders. In the present investigation, we evaluated the anti-asthmatic effects of schizandrin and its underlying mechanisms in an in vivo murine asthmatic model. To accomplish this, female BALB/c mice were sensitized and challenged with ovalbumin (OVA), and examined for the following typical asthmatic reactions: increased numbers of eosinophils and other inflammatory cells in bronchoalveolar lavage fluid (BALF); production of Th1 cytokines (such as tumor necrosis factor (TNF)-α in BALF); production of Th2 cytokines (such as interleukin IL-4 and IL-5) in BALF; presence of total and OVA-specific immunoglobulins (Ig)E in serum; presence of oxidative stress; hyperplasia of goblet cells in the lung; and marked influx of inflammatory cells into the lung. Our results collectively show that schizandrin exerts profound inhibitory effects on accumulation of eosinophils into the airways and reduces the levels of IL-4, IL-5, IFN-γ, and TNF-α in BALF. Additionally, schizandrin suppresses the production of reactive oxygen species (ROS) in a dose-dependent manner, and inhibits goblet cell hyperplasia and inflammatory cell infiltration in lung tissue. Thus, schizandrin has anti-asthmatic effects, which seem to be partially mediated by reduction of oxidative stress and airway inflammation, in a murine allergic asthma model. These results indicate that schizandrin may be an effective novel therapeutic agent for the treatment of allergic asthma.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclooctanes; Cytokines; Disease Models, Animal; Eosinophils; Female; Goblet Cells; Hyperplasia; Immunoglobulin E; Lignans; Lung; Mice; Mice, Inbred BALB C; Oxidative Stress; Polycyclic Compounds; Reactive Oxygen Species; Th1 Cells; Th2 Cells

Chronic airway inflammation is a hallmark of asthma, an immune-based disease with great societal impact. Honokiol (HNK), a phenolic neurotransmitter receptor (γ-aminobutyric acid type A) agonist purified from magnolia, has anti-inflammatory properties, including stabilization of inflammation in experimentally induced arthritis. The present study tested the prediction that HNK could inhibit the chronic inflammatory component of allergic asthma. C57BL/6 mice sensitized to and challenged with OVA had increased airway hyperresponsiveness to methacholine challenge and eosinophilia compared with naive controls. HNK-treated mice showed a reduction in airway hyperresponsiveness as well as a significant decrease in lung eosinophilia. Histopathology studies revealed a marked drop in lung inflammation, goblet cell hyperplasia, and collagen deposition with HNK treatment. Ag recall responses from HNK-treated mice showed decreased proinflammatory cytokines in response to OVA, including TNF-α-, IL-6-, Th1-, and Th17-type cytokines, despite an increase in Th2-type cytokines. Regulatory cytokines IL-10 and TGF-β were also increased. Assessment of lung homogenates revealed a similar pattern of cytokines, with a noted increase in the number of FoxP3(+) cells in the lung. HNK was able to alter B and T lymphocyte cytokine secretion in a γ-aminobutyric acid type A-dependent manner. These results indicate that symptoms and pathology of asthma can be alleviated even in the presence of increased Th2 cytokines and that neurotransmitter agonists such as HNK have promise as a novel class of anti-inflammatory agents in the treatment of chronic asthma.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Biphenyl Compounds; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Eosinophilia; Female; Fluorescent Antibody Technique; Hypersensitivity; Lignans; Lung; Mice; Mice, Inbred C57BL; Th2 Cells

Investigate into transport rate and retention rate transference of principal effective constituent in Shujin Kechuang capsule, a new development Chinese patent medicine for theraphy asthma.. HPLC was applied to analyze the content of ephedrine hydrochloride and honokiol and magnolol in crude drugs and 60% ethanol extracting solution and 25% concentrated solution,50% concentrated solution, 100% concentrated solution and finished product ( Shujin Kechuang capsule).. The transport rate of ephedrine hydrochloride and honokiol and magnolol is 56. 32%, 14. 43%, 14. 56% in the finished product respectively.. should be concentrate and desiccation in the condition that decompress and low temperature.

Topics: Asthma; Biphenyl Compounds; Capsules; Chromatography, High Pressure Liquid; Drug Combinations; Drugs, Chinese Herbal; Ephedra sinica; Ephedrine; Lignans; Magnolia; Plant Structures; Plants, Medicinal; Technology, Pharmaceutical

Magnolol and honokiol are the two major phenolic constituents of the plant medicine "Houpo" ( Magnolia obovata), which is used in the treatment of chest tightness and asthma. The aim of this study was to investigate the influence of magnolol and honokiol on smooth muscle tone in porcine trachea. Magnolol and honokiol (0.1 - 100 microM) inhibited carbachol- and high K +-induced muscle contractions in a concentration-dependent fashion, but did not affect basal muscle tension. After washout of these pretreatments, carbachol- and high K +-evoked muscle contractions were still abolished, suggesting that the inhibition was irreversible. Magnolol and honokiol also concentration-dependently decreased the Ca 2+-dependent muscle contraction induced by high K + depolarization. Ca 2+ channel antagonists attenuated carbachol-induced muscular response by approximately 30 %, but did not further potentiate the inhibitory actions of magnolol and honokiol on muscle contraction. However, the inhibitory effects of magnolol and honokiol on carbachol-evoked muscular contractile response were partially reversed after removal of Ca 2+ channel antagonist pretreatment. Alternatively, caffeine-elicited muscle contractions were not altered by magnolol, honokiol, and verapamil. In conclusion, the relaxant effects of magnolol and honokiol on porcine tracheal smooth muscle suggest an association with the blockade of Ca 2+ influx through voltage-operated Ca 2+ channels instead of Ca 2+ release from intracellular Ca 2+ stores. The magnolol- and honokiol-induced inhibitions on tracheal smooth muscle contraction may be relevant to the claimed therapeutic effects of the extract from magnolia bark and contribute to their pharmacological effects by acting as anti-asthmatic agents.

Topics: Animals; Asthma; Biphenyl Compounds; Bronchodilator Agents; Calcium; Carbachol; Dose-Response Relationship, Drug; Lignans; Magnolia; Male; Muscle Contraction; Muscle, Smooth; Phytotherapy; Potassium Chloride; Swine; Trachea; Verapamil

To identify the anti-allergic components contained in Saiboku-To, a herbal medicine for the treatment of bronchial asthma, we studied the effects of eight phenolic compounds, which have been identified as the major human metabolites of Saiboku-To, and three triterpenoids contained in Saiboku-To on the release of leukotriene (LT) from human polymorphonuclear leukocytes (PMLs) stimulated with Ca(2+)-ionophore A23,187. All phenolic compounds exhibited dose-dependent suppression on release of both LTB4 and LTC4, while triterpenoids did not show any effects, except for glycyrrhetinic acid, which selectively inhibited LTC4-release. The five phenolic compounds, magnolol, dihydroxydihydromagnolol, baicalein, medicarpine and davidigenin, were found to exert a marked inhibition on LTB4- and LTC4-release with IC50 values of 0.7-15.3 microM. The results suggest that the phenolic compounds contribute to the anti-allergic effects of Saiboku-To through suppression of LT-release from PMLs.

Topics: Anti-Asthmatic Agents; Asthma; Drugs, Chinese Herbal; Flavonoids; Humans; Leukotrienes; Lignans; Medicine, Kampo; Neutrophils

Occupational asthma due to western red cedar is associated with histamine release from basophils and mast cells on exposure to plicatic acid (PA), but the mechanisms underlying this response remain unclear. Specific kinase inhibitors were used to study the role of tyrosine and serine/threonine kinases in PA-induced histamine release from human basophils. Pretreatment with the tyrosine kinase inhibitor methyl 2,5-dihydroxy-cinnamate (MDHC) attenuated histamine release from basophils triggered by anti-IgE (29.8% inhibition; n = 15; P < 0.01) or grass pollen (48% inhibition; n = 6; P < 0.01). Inhibition was concentration-dependent and could be reversed by washing the cells in buffer, while the inactive stereoisomer of MDHC did not affect histamine release. In contrast, the protein kinase C inhibitor staurosporine did not affect histamine release by either anti-IgE or grass pollen. Pretreatment with MDHC partially inhibited PA-induced histamine release from basophils of 6/9 patients with red cedar asthma (25.4% vs 33.8%; P = NS). Staurosporine gave a similar level of inhibition of PA-induced histamine release (25.3% vs 33.8%; P = NS). Thus, signal transduction of the human basophil Fc epsilon RI appears to depend upon tyrosine kinase activation, but not on protein kinase C (serine/threonine kinase) activation. The lack of specific effect on plicatic acid-induced histamine release in basophils obtained from patients with occupational asthma due to western red cedar suggests that tyrosine kinases are not as important in this disease as in atopic asthma, and is consistent with the view that histamine release in red cedar asthma is largely IgE-independent.

Topics: Allergens; Antibodies, Anti-Idiotypic; Asthma; Basophils; Cinnamates; Environmental Exposure; Enzyme Activation; Enzyme Inhibitors; Histamine; Histamine Antagonists; Humans; Hypersensitivity; Lignans; Naphthols; Poaceae; Pollen; Protein-Tyrosine Kinases; Trees

T cells are known to play a major role in the pathogenesis of atopic allergic asthma, but it is less clear whether they are involved in occupational asthma caused by low molecular weight chemicals such as plicatic acid.. We sought to determine whether peripheral blood T cells from patients with western red cedar asthma (WRCA) recognize plicatic acid (PA) conjugated to human serum albumin (HSA) as judged by proliferation or cytokine production and to analyze the response to PA inhalation with flow cytometry.. Significant proliferative responses to PA-HSA were observed in eight of 33 patients with WRCA, none of 10 exposed nonasthmatic cedar workers, and one of 18 nonasthmatic control subjects. Two of 25 patients with WRCA also showed proliferative responses to unconjugated PA. All the WRCA responders were either currently exposed to cedar or had ceased exposure within the preceding 2 years. None of the four patients receiving oral steroids responded, but inhaled steroids did not seem to influence responsiveness. No correlations were found between the maximum stimulation response and any of the current FEV1 values, the current PC20 methacholine values, or the magnitude of the late asthmatic response to PA. Peripheral blood T-cell subset proportions and their degree of activation were similar in patients with WRCA and exposed control subjects. There was no change in T-cell phenotypes or their activation markers after PA inhalation challenge. In vitro, PA-HSA stimulation did not affect subset ratios but led to release of small amounts of IL-5 and IFN-gamma, with no detectable increase in IL-4.. PA-HSA-specific T lymphocytes seem to be present in small numbers in the peripheral blood of patients with WRCA and may respond to antigenic exposure by producing IFN-gamma and IL-5. However, the proportion of responding cells would appear to be lower than in comparable studies of atopic asthma.

Topics: Adult; Allergens; Asthma; Cells, Cultured; Humans; Lignans; Lymphocyte Activation; Middle Aged; Naphthols; Occupational Diseases; Plants; Serum Albumin; T-Lymphocytes

To identify the inhibitor of prednisolone metabolism contained in Saiboku-To, we conducted in-vitro experiments of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), using rat liver homogenate and cortisol as a typical substrate. We studied the effects of ten herbal constituents on 11 beta-HSD. Five herbal extracts showed inhibitory activity with Glycyrrhiza glabra > Perillae frutescens > Zizyphus vulgaris > Magnolia officinalis > Scutellaria baicalensis. This suggests that unknown 11 beta-HSD inhibitors are contained in four herbs other than G. glabra which contains a known inhibitor, glycyrrhizin (and glycyrrhetinic acid). Seven chemical constituents which have been identified as the major urinary products of Saiboku-To in healthy and asthmatic subjects were studied; magnolol derived from M. officinalis showed the most potent inhibition of the enzyme (IC50, 1.8 x 10(-4) M). Although this activity was less than that of glycyrrhizin, the inhibition mechanism (non-competitive) was different from a known competitive mechanism. These results suggest that magnolol might contribute to the inhibitory effects of Saiboku-To on prednisolone metabolism through inhibition of 11 beta-HSD.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Animals; Antineoplastic Agents, Phytogenic; Asthma; Biphenyl Compounds; Chromatography, High Pressure Liquid; Cortisone; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Glucocorticoids; Glycyrrhetinic Acid; Glycyrrhizic Acid; Hydrocortisone; Hydroxysteroid Dehydrogenases; Immunosuppressive Agents; Lignans; Liver; Male; Medicine, Kampo; Rats; Rats, Wistar

Occupational asthma due to Western red cedar is the most common form of occupational asthma in the Pacific Northwest and affects 4-13.5% of the exposed population. It has been shown to be caused by plicatic acid, a low molecular weight compound present uniquely in the wood. The mechanism of asthma induced by plicatic acid is not known, as specific IgG antibodies were found only in about 20% of patients. Sera from patients with red cedar asthma failed to passively sensitize human lung fragments of human basophils. Basophils from patients with this disease released histamine when challenged directly with plicatic acid in a specific manner. Immunologic mechanisms other than Type I hypersensitivity reaction are likely to be involved.

Topics: Allergens; Animals; Antibodies, Anti-Idiotypic; Asthma; Dust; Humans; Immunoglobulin E; Lignans; Naphthols; Occupational Diseases; Trees; Wood

Western red cedar asthma is the most common form of occupational asthma in the Pacific Northwest. Plicatic acid (PA) is the chemical component of Western red cedar that causes asthma. The role of immunologic processes involved in the PA-induced asthmatic reaction has not been established. To characterize the mechanisms of PA-induced asthmatic reaction, guinea pigs were sensitized to PA through biweekly injection of PA-ovalbumin conjugate with aluminum hydroxide as an adjuvant for a period of 6 months. Specific IgG1 antibodies to PA were detected in the blood 3 months after sensitization of animals. The level of specific IgG1 antibodies to ovalbumin after 6 months was about two times the level of specific IgG1 to PA. At 6 months, tracheal tissue from PA-ovalbumin-sensitized guinea pigs contracted after exposure to either PA or ovalbumin in vitro. The degree of contraction induced by PA was two to three times less than the contraction induced by ovalbumin. PA caused histamine, prostaglandin D2, and leukotriene D4 release from both lung mast cells and blood basophils. The amount of histamine and eicosanoids released by PA was also two to three times less than the amount of mediators released by ovalbumin. When the trachea of normal guinea pigs was passively sensitized with serum from PA-ovalbumin-sensitized guinea pigs, it contracted in response to PA or ovalbumin in an organ bath. When the serum of PA-ovalbumin-sensitized guinea pigs was depleted of immunoglobulins and then used for passive sensitization of normal trachea, no contraction was observed when challenged with PA, suggesting that IgG1 antibodies mediate the tracheal reaction to PA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Allergens; Animals; Asthma; Disease Models, Animal; Guinea Pigs; Immunization; Immunoglobulin G; In Vitro Techniques; Leukotriene D4; Lignans; Lung; Male; Muscle Contraction; Muscle, Smooth; Naphthols; Prostaglandin D2; Time Factors; Trachea; Trees

Saiboku-To is an anti-asthmatic herbal remedy which consists of ten herbal extracts. To investigate the clinical relationship between the effects and chemical components of Saiboku-To, a simple and sensitive high-performance liquid chromatographic method (HPLC) for determination of magnolol, one of the major urinary products, was developed. Organic solvent extraction of urinary magnolol was conducted by diatomaceous earth column rapid-flow fractionation using ethanol/dichloromethane (8/92, v/v). Recovery rates of magnolol were more than 99% with coefficient of variations less than 6% in the concentration range 9.7-970 ng mL-1. Subsequent HPLC determination of magnolol was achieved using a conventional silica-gel column, a mobile phase mixture of acetic acid/diethyl ether/n-hexane (0.2/17.0/82.8, v/v), and a UV-absorption detector set at 290 nm. Calibration was on the basis of peak height ratio between magnolol and flavone as an internal standard. The method was used to demonstrate excretion profiles of magnolol in healthy and asthmatic subjects following single administration of Saiboku-To.

Topics: Adult; Aged; Asthma; Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Histamine H1 Antagonists; Humans; Lignans; Male; Medicine, Kampo; Middle Aged

Saiboku-To, a mixture of ten different herbal extracts, has been used in Japan and Czechoslovakia for corticosteroid-dependent severe asthma to reduce the maintenance doses of corticosteroid. Magnolol has been considered to be an active component of Saiboku-To as an inhibitor of 11 beta-hydroxysteroid dehydrogenase and T-lymphocyte proliferation resulting in corticosteroid-sparing. To investigate the relationship between magnolol and the clinical effects of Saiboku-To, urinary magnolol excretion was compared in responders and non-responders under long-term Saiboku-To treatment. The clinical outcome of the Saiboku-To treatment was evaluated in nine asthmatic patients at 52 weeks after the onset of the treatment, using individual fluctuation of asthmatic points obtained from the patients' diary cards. Three patients whose clinical conditions were improved by the treatment were termed responders and six others were termed non-responders. The difference in the amounts of the total magnolol excreted were not significant; however, free (or non-conjugated) amounts of magnolol excreted in the responders were 7 times those in the non-responders (P < 0.05). These results suggest that the magnolol might be responsible for the therapeutic effect of Saiboku-To, indicating practical bioavailability in the responders.

Topics: Adult; Aged; Asthma; Biological Availability; Biphenyl Compounds; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Female; Histamine H1 Antagonists; Humans; Lignans; Male; Medicine, Kampo; Middle Aged

Occupational asthma caused by western red cedar (Thuja plicata) is a common problem in sawmill industries. The objective of this study was to examine the cellular and immunologic mechanisms of western red cedar asthma (WRCA) more closely.. Bronchial biopsy specimens, bronchoalveolar lavage (BAL) mast cells and peripheral blood basophils from patients with WRCA, patients with atopic asthma, and nonatopic control subjects were challenged in vitro with plicatic acid (PA), PA-human serum albumin conjugate (PA-HSA), grass pollen, or calcium ionophore.. PA (100 micrograms/ml) released histamine from the basophils of 9 of 11 patients with WRCA, 1 of 7 patients with atopic asthma, and 2 of 7 normal subjects. PA triggered histamine release from 10 of 11 bronchial biopsy specimens and 8 of 8 BAL samples from patients with WRCA. Interestingly, PA released histamine from BAL cells and bronchial biopsy specimens from 3 of 7 normal subjects but in none of the patients with atopic asthma. PA-HSA-induced histamine release from basophils and biopsy specimens was confined to patients with WRCA. PA-specific IgE was not detectable in serum from most patients with WRCA, and their serum did not transfer PA sensitivity to human lung fragments or lactate-stripped basophils. After pretreatment with anti-IgE in the absence of calcium, basophils from 14 subjects with WRCA still responded to PA (mean 64% to 67% of pretreatment response), whereas responses to grass pollen or anti-IgE were abolished.. This study confirms that PA releases histamine from bronchial mast cells of most patients with WRCA but not from those of patients with atopic asthma. The PA response of some normal subjects suggests that PA may have both specific and nonspecific actions on mast cells and basophils, whereas the serologic studies indicate histamine release in WRCA cannot simply be attributed to PA-specific IgE.

Topics: Adult; Allergens; Analysis of Variance; Asthma; Basophils; Bronchi; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Female; Humans; Immunoglobulin E; Lignans; Male; Naphthols; Occupational Diseases; Wood

Peak expiratory flow rates (PEF) are often used to confirm the diagnosis of occupational asthma. The records are usually analysed qualitatively, and this may lead to interobserver disagreement. In this study the diagnostic value of a qualitative assessment of change in PEF was compared with objective measures of change in PEF and the results of a specific inhalation challenge test with plicatic acid.. Twenty five patients with possible red cedar asthma recorded PEF six times a day for three weeks at work and for two weeks away from work and underwent a challenge test with plicatic acid at the end of the recording period. Patients were considered to have cedar asthma if the FEV1 after inhalation of plicatic acid was 15% or more below that on the control day. PEF was plotted against time and assessed qualitatively by three physicians. The graph was considered positive for cedar asthma if two of the three physicians agreed that PEF was lower at work than away from work. The 95% confidence interval for variation in PEF between periods at work and away from work was also obtained from 15 asthmatic patients without occupational asthma. Differences in PEF between periods at work and away from work were considered positive for occupational asthma in the patients exposed to cedar when they were outside the 95% confidence interval for variations in PEF in the 15 patients whose asthma was nonoccupational.. Of the 25 men studied, 15 had a positive response to plicatic acid. The qualitative PEF analysis had a sensitivity of 87% and a specificity of 90% in confirming red cedar asthma as diagnosed by the specific challenge test. Among the objective methods tested, only the difference in mean PEF between the maximum PEF at weekends and the minimum PEF on working days had a sensitivity (93%) greater than that of the qualitative method and a similar specificity.. The qualitative assessment of PEF is a good diagnostic test for cedar asthma. Only one objective method of PEF analysis proved to be slightly more sensitive than the qualitative method and similar in specificity.

Topics: Asthma; Bronchial Provocation Tests; Humans; Lignans; Lung; Male; Naphthols; Occupational Diseases; Peak Expiratory Flow Rate; Predictive Value of Tests; Wood

Occupational asthma due to Western Red Cedar (WRCA) is attributed to sensitization to plicatic acid (PA), but does not appear to be dependent on PA-specific IgE antibodies. Exposure to PA induces histamine release in vivo and in vitro, so if IgE is not important, other mechanisms of histamine release must presumably operate in WRCA. To explore the possible role of histamine-releasing factors in WRCA, peripheral blood mononuclear cells were obtained and cultured with PA, PA-albumin conjugate plicatic acid-human serum albumin (PA-HSA), grass pollen or Concanavalin A using a standard histamine releasing factor (HRF) generation protocol. Supernatants were dialysed to remove endogenous histamine and then assayed for histamine releasing activity using human basophils as targets and a Con A-induced bulk supernatant as an internal HRF standard. In contrast to some previous reports, spontaneous HRF release from the peripheral blood mononuclear cells (PBMC) of WRCA patients (n=9) and atopic asthmatic subjects (n=5) was not elevated compared with the non-asthmatic controls (n=11; five atopic and six non-atopic). Both PA and PA-HSA induced the production of small amounts of HRF by PBMC of WRCA patients, but a similar degree of HRF generation was also observed in PBMC from the atopic asthmatic, atopic nonasthmatic, and non-atopic subjects. In contrast, grass pollen induced the production of HRF by PBMC from the subjects with positive skin tests to grass pollen but not by PBMC of non-atopic subjects, confirming that our methods and assay were capable of detecting antigen-specific HRF production. Since neither PA nor PA-HSA induced significantly elevated HRF production from PBMC of WRCA patients, it seems unlikely that PA-induced HRFs play a substantial role in the pathogenesis of WRCA.

Topics: Adult; Allergens; Antibody Specificity; Asthma; Basophil Degranulation Test; Biological Factors; Bronchial Provocation Tests; Concanavalin A; Dust; Female; Histamine Release; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Leukocytes, Mononuclear; Lignans; Male; Middle Aged; Naphthols; Occupational Diseases; Plant Lectins; Poaceae; Pollen; Serum Albumin; Trees; Wood

It is unknown whether factors such as the nature of the agent, gender, age, atopy, smoking habits, continuous or noncontinuous exposure, and pattern of asthmatic reaction can influence the rate of development of symptoms in subjects with occupational asthma. We compared several clinical and functional parameters among three groups of subjects with occupational asthma caused by Western red cedar (group 1, n = 433), isocyanates (group 2, n = 107), and high molecular weight agents acting through an IgE-mediated mechanism (group 3, n = 121). Survival analysis showed that the three curves relating years of exposure before onset of symptoms to the proportion of subjects without symptoms were significantly different in two respects: (1) almost 40% of subjects in groups 1 and 2 as compared with 20% of subjects in group 3 became symptomatic within 1 year of exposure; (2) after 5 years of exposure, the rate of sensitization was slower for subjects in groups 2 and 3 as compared with those in group 1. Having a nonimmediate reaction at the time of specific inhalation challenges, being continuously exposed and being younger slightly increased the risk at each time point on the curve of developing symptoms in subjects with occupational asthma. These data suggest that the natural history for onset of occupational asthma is different depending on the sensitizing agent. Factors such as age, type of exposure, and pattern of reaction on exposure to the agent also modulate the rate of development of this condition.

Topics: Adult; Allergens; Asthma; Cyanates; Female; Forced Expiratory Volume; Humans; Hypersensitivity; Hypersensitivity, Immediate; Lignans; Male; Middle Aged; Molecular Weight; Naphthols; Occupational Diseases; Smoking

After an average follow-up of 6.5 yr (range 1 to 13), 48 of 48 patients with cedar asthma, who were still working in the same industry, were re-examined. In all of them, the diagnosis of cedar asthma had been confirmed with a specific challenge inhalation test with plicatic acid. We graded the severity of asthma symptoms and the requirement for antiasthma medications at the time of diagnosis and at the time of follow-up visit. Spirometry and measurement of airway responsiveness to methacholine (PC20 methacholine) were also done on both visits. The increase or decrease in asthma symptoms, medications requirement, FEV1 and PC20 methacholine between the follow-up and the diagnostic visit were used to determine the outcome of the patients. Using these parameters, 10.4% of patients improved, 62.5% remained stable, 37.5% deteriorated, and none recovered. Among the characteristics of the patients observed at the time of diagnosis, the age of the patient, the atopic status, smoking habit, and the presence of specific IgE to plicatic acid were not useful in predicting the eventual outcome. Reduction of exposure by transfer to a less dusty job and the use of an airstream helmet did not prevent deterioration of asthma. Only the use of the twin-cartridge respirator was associated with a favorable outcome. We conclude that among cedar asthmatics who remained exposed to cedar dust for an average of 6.5 yr, over one-third showed marked deterioration of their asthma symptoms. There is also no way to predict who will deteriorate. A decrease in the amount of exposure to cedar dust does not prevent deterioration of asthma. This suggests that the ideal management of cedar asthma is removal from exposure.

Topics: Allergens; Asthma; British Columbia; Bronchial Provocation Tests; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Lignans; Male; Methacholine Chloride; Methacholine Compounds; Naphthols; Occupational Diseases; Palliative Care; Remission Induction; Surveys and Questionnaires; Vital Capacity; Wood

The diagnosis of red cedar asthma is usually confirmed by a specific challenge with plicatic acid, the compound responsible for the disease. We performed this study to determine the sensitivity and specificity of two other diagnostic tests, prolonged recording expiratory flow rate (PEFR) and measurement of bronchial responsiveness (provocative dose of methacholine causing a 20% fall in FEV1 [PC20 methacholine]). Twenty-three patients with suspected cedar asthma participated in the study. The patients recorded PEFR during 2 weeks away from work and 3 weeks at work. PC20 was measured both at the end of the nonworking and working period. An obvious decrease in PEFR in 2 of 3 working weeks, when PEFRs of weekends or holidays were compared (by visual inspection of the PEFR recording), and a decrease in PC20 by more than a twofold dilution, when the patient returned to work, were considered as positive tests for cedar asthma. Plicatic acid challenge test was performed at the end of the study; 14 patients reacted, whereas nine patients did not. With the results of the plicatic acid challenge test as the gold standard, the sensitivity and specificity of PEFR recordings were 86% and 89%; changes in PC20, 62% and 78%; and 93% and 45% for a positive clinical history. The combination of PEFR and clinical history revealed a 100% sensitivity with a 45% specificity. Combination of PEFR and PC20 did not improve the diagnostic accuracy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Allergens; Asthma; Bronchial Provocation Tests; False Positive Reactions; Forced Expiratory Volume; Humans; Lignans; Methacholine Chloride; Methacholine Compounds; Naphthols; Occupational Diseases; Peak Expiratory Flow Rate; Time Factors; Trees

Bronchoalveolar lavage (BAL) was performed before and 10 minutes after inhalation challenge with plicatic acid in five patients with red cedar asthma. There was a significant release of histamine and leukotriene E4 into the BAL fluid in all the patients after challenge. Inhalation challenge with methacholine in six patients with nonoccupational asthma and inhalation challenge with plicatic acid in two subjects without asthma did not result in the release of mediators in the BAL fluid. These studies provide direct evidence that plicatic acid-induced bronchoconstriction was accompanied by increased levels of histamine and leukotriene E4 release, whereas a nonimmunologic induction of bronchoconstriction did not induce such local mediator release. BAL may provide a useful means of studying the pathogenesis of occupational asthma caused by exposure to low-molecular-weight compounds.

Topics: Adolescent; Adult; Allergens; Asthma; Bronchi; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Histamine Release; Humans; Leukotrienes; Lignans; Middle Aged; Naphthols; Occupational Diseases; Trees

Although late bronchospastic reactions after exposure to antigenic and sensitizing agents usually significantly alter bronchial responsiveness to histamine or methacholine, presumably by causing bronchial inflammation, isolated immediate bronchospastic reactions do not induce such changes. We studied three subjects who demonstrated different patterns of reaction. The first individual was diagnosed as having occupational asthma to red cedar. This was confirmed by specific inhalation challenges that resulted in late bronchospastic reaction. No significant changes in the provocative concentration of histamine causing a 20% fall in FEV1 (PC20) were found 1 day after this reaction. Two weeks later, serial assessments (five and six, respectively) of PC20 histamine were recorded on control days and up to 48 hours after exposure to plicatic acid, which caused a late bronchospastic reaction with a maximum fall of 37% in FEV1. No significant changes in PC20 were found; the maximum variations on control days were 0.36 to 0.74 mg/ml, and on active days, from 0.37 to 0.59 mg/ml. By contrast, two other subjects, who demonstrated isolated immediate reactions after exposure to diphenylmethane diisocyanate, had significant changes in PC20 histamine and methacholine, in one subject from 3.1 mg/ml to 0.6 mg/ml 8 hours after exposure, and in the other subject, from 61.0 to 7.4 mg/ml 7 hours after exposure, with recovery during the next few days. These examples demonstrate that the pattern of nonspecific bronchial responsiveness after immediate and late bronchospastic reactions can be different from what has previously been described. Immediate bronchospastic reactions may lead to bronchial hyperresponsiveness, whereas late asthmatic reactions do not always induce changes in bronchial responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Cyanates; Forced Expiratory Volume; Histamine; Humans; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Isocyanates; Lignans; Male; Methacholine Chloride; Methacholine Compounds; Middle Aged; Naphthols; Occupational Diseases

Two hundred twenty-seven workers in a western red cedar sawmill underwent methacholine bronchoprovocation testing at least 2 times during 3 surveys over a 2-yr period. At the first survey, workers completed a respiratory and occupational questionnaire, performed spirometry, gave serum for measurement of plicatic acid-specific IgE antibodies by radioallergosorbent testing, and had skin prick tests to detect atopy. Bronchial hyperresponsiveness was present initially in 18% of the workers. Approximately 15% of those with initially no hyperresponsiveness developed hyperresponsiveness during the follow-up period; 15% of those with initial hyperresponsiveness also lost it during follow-up. Development of hyperresponsiveness tended to coincide with a decrease in level of pulmonary function, whereas loss of hyperresponsiveness was associated with improvement in pulmonary function. Workers with either persistent bronchial hyperresponsiveness or with varying responsiveness had a higher prevalence of plicatic acid IgE antibodies and lower levels of initial pulmonary function than did workers with persistent nonresponsiveness. Workers with persistent hyperresponsiveness had higher initial estimated total airborne dust exposure than did other workers. Age, duration of sawmill employment, atopy, race, and cigarette smoking did not influence the occurrence of hyperresponsiveness. Levels of plicatic-acid-specific IgE antibodies did not change substantially over the 2 yr. These results indicate that immunologic sensitivity to plicatic acid and change in airway caliber are associated with the occurrence of bronchial hyperresponsiveness in cedar workers.

Topics: Allergens; Asthma; British Columbia; Bronchial Diseases; Bronchial Provocation Tests; Humans; Hypersensitivity, Immediate; Lignans; Longitudinal Studies; Male; Methacholine Chloride; Methacholine Compounds; Naphthols; Occupational Diseases; Wood

In order to investigate the relationship between the pattern of response (immediate, late and dual) to specific bronchial challenge test with plicatic acid or red cedar extract and the clinical features of asthma, 332 patients with asthma induced by western red cedar dust were examined at the time of diagnosis. Specific challenge test induced in thirty-one patients (9.3%) an isolated immediate reaction, in 144 patients (43.4%) an isolated late reaction and in 157 patients (47.3%) a dual reaction. Patients with a dual reaction had a longer period of exposure to red cedar dust between the onset of the respiratory symptoms and the time of the definitive diagnosis, a lower FEF 25-75% and a greater degree of non-specific bronchial hyperresponsiveness compared to patients with isolated immediate or isolated late reactions; the difference in bronchial hyperresponsiveness to methacholine among the three groups persisted when the values were adjusted for the different baseline value of FEV1. There was no difference in the prevalence of specific serum IgE antibodies to plicatic acid-human serum albumin conjugate among the three groups of patients with different type of response to red cedar. Except for the greater degree of non-specific bronchial hyperresponsiveness, patients with isolated late reactions were not different from those with isolated immediate reactions in other clinical findings. These findings indicate that a dual reaction in patients with occupational asthma due to simple chemical agents is indicative of a greater severity of disease at diagnosis. The pathogenetic mechanism of various types of asthmatic reaction is unknown and it is likely to be different between isolated immediate and isolated late reactions.

Topics: Adult; Allergens; Asthma; Bronchial Provocation Tests; Humans; Immunoglobulin E; Lignans; Methacholine Chloride; Methacholine Compounds; Middle Aged; Naphthols; Occupational Diseases; Respiratory Function Tests; Skin Tests; Time Factors; Wood

Plasma histamine levels were measured by radio-enzymatic technique in seven patients following 10 challenges: five methacholine challenge tests, four antigen inhalation challenge tests, and one oral aspirin challenge test. Baseline plasma histamine was the same in all patients except in the aspirin-challenged patient, who had a higher baseline histamine level. There was no statistical change in the level of histamine throughout the test in either the methacholine-challenged or the antigen-challenged patients, whereas there was a marked increase in histamine levels in the aspirin challenged patient. A possible explanation is that methacholine and antigen are inhaled and therefore have primarily local effects on the lung, whereas oral aspirin has a systemic effect with consequently systemic changes in histamine which are detectable as changes in plasma level.

Topics: Adult; Antigens; Aspirin; Asthma; Female; Histamine; Humans; Hypersensitivity, Immediate; Lignans; Male; Methacholine Chloride; Methacholine Compounds; Middle Aged; Naphthols; Respiratory Function Tests; Triticum

We describe a rabbit model for the study of the immunogenicity and allergenicity of plicatic acid (PA), the small molecular weight compound in western red cedar responsible for occupational asthma in exposed workers. Specific anti-PA IgE as well as IgG antibodies could be raised, depending on the method of immunization. The sensitized rabbits reacted to antigenic challenge with PA-protein conjugates intravenously, with increases in respiratory frequency and pulmonary resistance. This animal model may be used for the further elucidation of the mechanism of occupational asthma induced by small molecular weight chemical compounds.

Topics: Animals; Antibody Formation; Asthma; Disease Models, Animal; Immunoglobulin E; Immunoglobulin G; Lignans; Naphthols; Rabbits; Respiratory Hypersensitivity

A total of 232 patients with red cedar asthma diagnosed by inhalation provocation tests were observed an average of 4 years after the initial diagnosis. The status during the follow-up examination was as follows: 96 patients continued to work with red cedar, and 136 left the industry and had no further exposure to red cedar in their jobs or hobbies. Of the 136 patients who left the industry, only 55 (40.4%) recovered completely, whereas the remaining 81 (59.6%) continued to experience attacks of asthma of varying severity. The initial pulmonary function tests were significantly higher among the asymptomatic group compared to the symptomatic group (FEV1 99.3 +/- 2.7% versus 90.5 +/- 2.2% predicted, respectively). Methacholine PC20 during the initial examination was higher among the asymptomatic group than in the symptomatic group (1.46 +/- 3.96 mg/ml versus 0.77 +/- 4.52 mg/ml, respectively). These findings indicate that the patients in the asymptomatic group were diagnosed at an earlier stage of the disease. This observation was confirmed by the significantly shorter duration of symptoms before diagnosis among the asymptomatic patients compared to the symptomatic patients (1.6 +/- 1.9 versus 2.6 +/- 4.3 years). Race, smoking status, immediate skin reactivity, and presence of plicatic acid-specific IgE antibodies did not influence the outcome of these patients. Of the 96 patients who continued to work with red cedar, 47 were exposed daily, whereas 41 were exposed intermittently.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Asthma; Bronchi; Bronchial Provocation Tests; Female; Follow-Up Studies; Humans; Lignans; Male; Middle Aged; Naphthols; Occupational Diseases; Respiratory Function Tests

To investigate the sequence of cellular and protein changes after a late asthmatic reaction (LAR), bronchial lavage was carried out in 44 patients with red cedar asthma at different time intervals after bronchial challenge with plicatic acid. The results were compared to five patients with red cedar asthma who became asymptomatic after removal from exposure to red cedar for more than 2 months and 31 healthy subjects without asthma. The LAR was found to be associated with an increase in eosinophils in the lavage fluid, an increase in sloughing of bronchial epithelial cells, and an increase in degenerated cells consisting mainly of degenerated epithelial cells and alveolar macrophages. There was an increase in vascular permeability as reflected by an increase in albumin in the lavage fluid. Although there was a slight but significant increase in neutrophils 48 hours after bronchial challenge, neutrophil infiltration was not a prominent feature earlier. The potential role of loss of epithelial cells to account for an increase in nonspecific bronchial hyperresponsiveness after an LAR was discussed.

Topics: Adult; Asthma; Biopsy; Bronchi; Bronchial Provocation Tests; Female; Humans; Lignans; Male; Naphthols; Pollen; Therapeutic Irrigation; Trees

In a cross-sectional survey of 652 workers in a western red-cedar sawmill, we obtained data on symptoms, pulmonary function, immediate skin reactivity to common allergens, nonspecific bronchial responsiveness, total IgE level, and sensitization to plicatic acid conjugated with human serum albumin as measured by RAST. Dust exposure was estimated by personal and area sampling for total dust during a work shift and cumulative exposure by duration of employment. Seven percent of the workers had an elevated RAST, and 20% had nonspecific bronchial hyperresponsiveness. Elevation in RAST was associated with bronchial hyperresponsiveness. Almost half (46%) of the workers with RAST elevation had bronchial hyperresponsiveness compared to 18% in workers with no RAST elevation. The association was unaffected by total IgE level or by limiting the analysis to workers without respiratory symptoms and was most apparent in younger workers. Bronchial hyperresponsiveness was associated with increased prevalence of respiratory symptoms as well as with lower levels of pulmonary function. The likelihood of bronchial hyperresponsiveness increased with increasing age but was unrelated to the dust-exposure concentration. RAST elevation was unrelated to employment duration or dust exposure and was not associated with an increased prevalence of symptoms or lower levels of pulmonary function independent of bronchial hyperresponsiveness. We conclude that plicatic acid-specific IgE and nonspecific bronchial hyperresponsiveness are associated in western red-cedar workers and that this association may reflect a causal connection.

Topics: Adult; Antibody Specificity; Asthma; Bronchi; Dust; Humans; Immunoglobulin E; Lignans; Male; Methacholine Compounds; Naphthols; Occupational Diseases; Radioallergosorbent Test; Respiratory Function Tests

A worker developed symptoms of work-related asthma a few weeks after starting to work in a sawmill where eastern white cedar (Thuja occidentalis) was transformed into shingles. The diagnosis of occupational asthma was confirmed by monitoring of peak expiratory flow rates and bronchial responsiveness to histamine off work and at work, and specific inhalation challenges in the laboratory that demonstrated an isolated late asthmatic reaction after exposure for 4 hours to the wood dust. Specific inhalation challenges with western red cedar (thuja plicata) for 2 hours and plicatic acid (PA) for 7 minutes also caused an isolated late asthmatic reaction. Elevated specific IgE levels to PA were present. Antiserum was produced in rabbits that were immunized with PA conjugated to human serum albumin. With this antiserum in inhibition experiments, cross-reactivity between western red cedar and eastern white cedar, both belonging to the family of arborvitae, was found. It is estimated that eastern white cedar contains approximately half the amount of PA present in western red cedar.

Topics: Adult; Allergens; Asthma; Bronchial Provocation Tests; Female; Forced Expiratory Volume; Humans; Lignans; Naphthols; Occupational Diseases; Radioallergosorbent Test

To investigate the optimal lavage technique to study the airway response in patients with asthma, differential volume lavage was carried out in 22 normal subjects and 18 patients with red cedar asthma. Ten ml of fluid was instilled into a main-stem bronchus followed by 5, 10, 20, 50 and 100 ml into different segmental bronchi. Small volume lavage (less than 20 ml) in a main stem bronchus or a segmental bronchus recovered more epithelial cells and neutrophils while a lavage volume of 20-100 ml in a segmental bronchus recovered more lymphocytes, alveolar macrophages, albumin, IgG and alpha 1-antitrypsin. In patients with asthma, a higher proportion of epithelial cells was observed in the 20 ml segmental bronchus lavage 24 to 48 hours after bronchial challenge with plicatic acid, the chemical compound responsible for red cedar asthma. There was an increase in eosinophils and IgG with all volume lavages, but the changes were most marked in the 10 ml main bronchus lavage and the 10 and 20 ml segmental bronchus lavage. The results show the importance of using a systematic lavage protocol to characterize the cellular and protein changes in the airways of patients with asthma. A single volume lavage in one site may not encompass all the changes observed.

Topics: Adolescent; Adult; Asthma; Bronchi; Bronchial Provocation Tests; Cell Count; Humans; Lignans; Middle Aged; Naphthols; Proteins; Therapeutic Irrigation

We studied the relationship between specific IgE antibodies, nonspecific bronchial reactivity to methacholine, and the type of asthmatic reaction in patients with red cedar asthma. The level of circulating specific IgE antibodies (expressed as RAST ratios) was not related to the type of asthmatic reaction, the degree of nonspecific bronchial hyperreactivity [expressed by the provocative concentration of methacholine producing a 20% decrease in the forced expiratory volume in 1 sec (PC20)] or the index of reactivity to plicatic acid. On the other hand, methacholine PC20 was found to correlate with the index of reactivity to plicatic acid in the late asthmatic reaction (LAR) and both the immediate and late components of the dual asthmatic reaction (DAR). Development of the LAR is associated with increase in nonspecific bronchial hyperreactivity. Repeated inhalation challenge with plicatic acid in eight patients with LAR resulted in DAR in all. The results suggest that the mechanism responsible for the LAR is associated with an increase in nonspecific bronchial reactivity; furthermore, the immediate component of DAR could also be related to heightened bronchial hyperreactivity.

Topics: Adult; Asthma; Bronchial Provocation Tests; Forced Expiratory Volume; Humans; Immunoglobulin E; Lignans; Methacholine Chloride; Methacholine Compounds; Middle Aged; Naphthols; Radioallergosorbent Test; Time Factors

Topics: Adult; Asthma; British Columbia; Bronchi; Dust; Follow-Up Studies; Histamine Release; Humans; Lignans; Middle Aged; Naphthols; Occupational Diseases; Time Factors; Wood

The presence of specific IgE antibodies in the serum of patients with occupational asthma resulting from exposure to western red cedar (RCA) was studied by a radioallergosorbent test (RAST). The antigen matrix used in the RAST was either a conjugate of Sepharose particles with antigens in a crude cedar extract or with plicatic acid, the major haptenic component of cedar antigens. Of eighteen patients with clinical RCA and positive reaction to antigenic bronchoprovocation, eight were found to have abnormal RAST values. By appropriate absorption experiments, the serum RAST activity was shown to represent cedar antigen-specific IgE antibodies. No significant RAST activity was detected in the serum specimens from sixteen control subjects or from ten patients with negative bronchoprovocation-reaction to antigenic challenge. These results suggest that IgE antibody-mediated allergic reaction may be an important pathogenetic factor in RCA.

Topics: Allergens; Asthma; Bronchial Provocation Tests; Epitopes; Humans; Immunoglobulin E; Lignans; Naphthols; Occupational Diseases; Poaceae; Pollen; Radioallergosorbent Test; Wood

Plicatic acid, a low-molecular-weight compound responsible for western red cedar (Thuja plicata) asthma was tested for its ability to activate complement and to generate chemotactic activity from pooled normal human serum (NHS). Dose-dependent complement consumption was found as determined by hemolytic assay (CH50). Activation of complement by plicatic acid was also confirmed by the demonstration of conversion of C3 to C3b on immunoelectrophoresis. This activation was completely prevented by pretreating the serum with either edetate (EDTA) or ethylene glycol tetraacetic acid (EGTA), suggesting that complement was activated via the classical pathway. No conversion of factor B was seen in any of the samples. Leukocyte chemotactic activity was also generated when serum was incubated with plicatic acid. The consumption of C3 and CH50 was unimpaired in two samples of serum from patients with severe, untreated hypogammaglobulinemia and thus appears to be immunoglobulin independent. These observations suggest that plicatic acid could activate complement in vivo, thereby inducing an inflammatory response in the airways and contributing to the higher prevalence of industrial chronic bronchitis in exposed subjects. The pathogenetic role of complement activation in red cedar asthma has yet to elucidated.

Topics: Animals; Asthma; Carboxylic Acids; Chemotaxis, Leukocyte; Complement Activation; Complement C3; Edetic Acid; Egtazic Acid; Humans; Immunoelectrophoresis; Lignans; Naphthols; Rabbits; Sheep; Trees; Zymosan